COPPER METABOLISM HENDRA WIJAYA Esa Unggul University Okt 2012

Copper in food Seafood Nuts, whole grains, seeds, legumes Organ meats, shellfish, whole-grain products, mushrooms.

Cu FUNCTION Energy Production Cytochrome c oxidase is a multi-subunit complex containing copper and iron and is essential for oxidative phosphorylation. Connective tissue formation Lysyl oxidase is a cuproenzyme essential for stabilization of extracellular matrixes. Enzymatic cross-linking of collagen and elastin. Iron metabolism Ferroxidase I (ceruloplasmin) and ferroxidase II, oxidize ferrous iron to ferric iron. Central nervous system Dopamine monooxygenase (DMO) requires copper as cofactor and ascorbate as electron donor. It catalyzes conversion of dopamine to norepinephrine, important neurotransmitter. Monoamine oxidase catalyzes the degradation of serotonin in the brain and is involved in the metabolism of catecholamine. Melanin synthesis Tyrosinase is copper-containing enzyme, present in melanocytes and catalyzes synthesis of melanin. Antioxidant functions SODs (superoxide dismutase) are Cu and Zn containing enzymes that convert superoxide radical to H2O2. Regulation of gene expression Cu-dependent proteins act as transcription factors

Enzyme contain copper as cofactor

Human Copper metabolism

Human Copper metabolism

Human Copper metabolism

Human Copper metabolism

Copper absorption in humans Copper metabolism in humans. (A) Model for human Cu absorption and distribution at the organ and tissue level. Dietary Cu is primarily absorbed from the stomach and small intestine. hCTR1, a putative high affinity Cu transporter, may transport Cu into intestinal mucosal cells and MNK is required for Cu transport into the portal circulation. MNK is a P-type ATPase defective in Menkes patients in which Cu is accumulated in intestinal epithelial cells. Once entering the plasma, Cu is bound with albumin and histidine in the portal blood and rapidly deposited in the liver where hCTR1 may play a role in this process. Ceruloplasmin, a major Cu-containing protein in plasma, is synthesized in the liver with the incorporation of Cu by the WND protein in the secretory pathway and has ferroxidase activity that is critical for iron metabolism. WND has high homology with MNK and is defective in Wilson’s disease patients who suffer from Cu accumulation in liver. Biliary excretion via the gall bladder is the major route of Cu elimination from the body and a small amount of Cu is found in urine. Heph is a membrane bound ceruloplasmin/Fet3 homologue required for iron egress from the intestine that is defective in sla mice, a model for sex-linked anemia. (B) Model for human Cu uptake and distribution at the cellular level. Tissue uptake of Cu is likely mediated by the hCTR1 Cu transporter. Once transported by hCTR1, the small cytoplasmic Cu chaperones (hCOX17, HAH1, CCS) distribute Cu to specific cellular compartments for the incorporation of Cu into Cu-requiring proteins. hCOX17, HAH1 and CCS deliver Cu to the mitochondria, secretory compartment, and Cu, Zn SOD, respectively. Cu chaperones for metallothionein and the nucleus have not been identified. In tissues other than the liver, MNK transports Cu delivered by HAH1 into the TGN for incorporation of Cu into secretory proteins. Although it is not known how these Cu chaperones take Cu transported from outside, the Atx1 and CCS Cu chaperones directly interact with their specific target molecule to surrender Cu. Cu stimulates the trafficking of MNK from the TGN to the plasma membrane where it may be involved in Cu efflux. In hepatic cells, WND, the Wilson’s disease protein is localized in the TGN. Elevated Cu levels stimulates its trafficking from the TGN to an unknown cytosolic vesicular compartment. Peña M M O et al. J. Nutr. 1999;129:1251-1260 ©1999 by American Society for Nutrition

Copper absorption in humans

Absorption, Metabolism, & Regulation of Copper Absorbed in small intestine & stomach mediated by specific transporters:metal binding protein metallothionein (Cu2+ ions are highly insoluble). Influenced by Cu status Copper circulates bound to ceruloplasmin Ceruloplasmin (CP) is a glycoprotein, copper-dependent ferroxidase (95% of the total copper in human plasma), oxidizes Fe2+ to Fe3+ in gastrointestinal iron absorption mechanism. Relative tissue distribution of copper reflects levels of cuproenzymes Excretion occurs via transport of copper into bile and elimination in feces

Uptake of Copper by hepatocyte Model of Cu uptake and metabolism in hepatocytes: Cu cross the plasma membrane through Ctrl1 (copper transporter1) or DMT1 (divalent metal transporter1) to the trans Golgi network (TGN) by chaperone Hah1. Chaperone protein Ccs delivers Cu to cytosolic Cu/Zn SOD. Cox17 delivers Cu to mitochondria for cytochrome c oxidase. Carrol et all, 2004)

Copper transport

Copper intake

Copper Deficiency Anemia: decreased iron absorption Depigmentation of hair or wool Black sheep are sometimes kept as indicators of marginal Cu deficiency Loss of wool crimp (“steely” wool) Bone disorders Central nervous lesions with muscular incoordination neutropenia and leukopenia bone demineralization failure of erythropoiesis

Induced Copper Deficiency Caused by relatively high levels of Mo and/or S Site of interaction is in the rumen Formation of insoluble Cu salts including sulfides and thiomolybdates Net effect is decreased Cu absorption

Induced Copper Toxicity Occurs with “normal” dietary levels of Cu and “low” levels of Mo and S Accumulates in liver